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The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway

The A2A adenosine receptor (A2AR)-mediated immunosuppression is firmly implicated in the life-saving down-regulation of collateral tissue damage during the anti-pathogen immune response and in highly undesirable protection of cancerous tissues during anti-tumor immune response. Therefore, depending...

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Autores principales: Ohta, Akio, Kini, Radhika, Ohta, Akiko, Subramanian, Meenakshi, Madasu, Manasa, Sitkovsky, Michail
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389649/
https://www.ncbi.nlm.nih.gov/pubmed/22783261
http://dx.doi.org/10.3389/fimmu.2012.00190
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author Ohta, Akio
Kini, Radhika
Ohta, Akiko
Subramanian, Meenakshi
Madasu, Manasa
Sitkovsky, Michail
author_facet Ohta, Akio
Kini, Radhika
Ohta, Akiko
Subramanian, Meenakshi
Madasu, Manasa
Sitkovsky, Michail
author_sort Ohta, Akio
collection PubMed
description The A2A adenosine receptor (A2AR)-mediated immunosuppression is firmly implicated in the life-saving down-regulation of collateral tissue damage during the anti-pathogen immune response and in highly undesirable protection of cancerous tissues during anti-tumor immune response. Therefore, depending on specific clinical situation there is a need to either weaken or strengthen the intensity of A2AR signal. While the A2AR-mediated immunosuppression was shown to be T cell autonomous in studies of effector T cells, it was not clear how A2AR stimulation affects regulatory T cells (Treg). Here we show in parallel assays that while A2AR stimulation on T cells directly inhibits their activation, there is also indirect and longer-lasting T cell inhibitory effect through modulation of Treg. A2AR stimulation expanded CD4(+) CD25(hi) FoxP3(+) cells, which also express CD39, CD73, and CTLA-4. Treg cultured with A2AR agonist showed increased expression of CTLA-4 and stronger immunosuppressive activity. There was a significant increase of Treg cell number after A2AR stimulation. The CD4(+) FoxP3(+) population contained those induced from CD4(+) CD25(−) cells, but CD4(+) FoxP3(+) cells predominantly derived from CD4(+) CD25(+) natural Treg. Thus, A2AR stimulation numerically and functionally enhanced Treg-mediated immunosuppressive mechanism. These data suggest that the A2AR-mediated stimulation of lymphocytes using A2AR agonists should be considered in protocols for ex vivo expansion of Treg before the transfer to patients in different medical applications.
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spelling pubmed-33896492012-07-10 The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway Ohta, Akio Kini, Radhika Ohta, Akiko Subramanian, Meenakshi Madasu, Manasa Sitkovsky, Michail Front Immunol Immunology The A2A adenosine receptor (A2AR)-mediated immunosuppression is firmly implicated in the life-saving down-regulation of collateral tissue damage during the anti-pathogen immune response and in highly undesirable protection of cancerous tissues during anti-tumor immune response. Therefore, depending on specific clinical situation there is a need to either weaken or strengthen the intensity of A2AR signal. While the A2AR-mediated immunosuppression was shown to be T cell autonomous in studies of effector T cells, it was not clear how A2AR stimulation affects regulatory T cells (Treg). Here we show in parallel assays that while A2AR stimulation on T cells directly inhibits their activation, there is also indirect and longer-lasting T cell inhibitory effect through modulation of Treg. A2AR stimulation expanded CD4(+) CD25(hi) FoxP3(+) cells, which also express CD39, CD73, and CTLA-4. Treg cultured with A2AR agonist showed increased expression of CTLA-4 and stronger immunosuppressive activity. There was a significant increase of Treg cell number after A2AR stimulation. The CD4(+) FoxP3(+) population contained those induced from CD4(+) CD25(−) cells, but CD4(+) FoxP3(+) cells predominantly derived from CD4(+) CD25(+) natural Treg. Thus, A2AR stimulation numerically and functionally enhanced Treg-mediated immunosuppressive mechanism. These data suggest that the A2AR-mediated stimulation of lymphocytes using A2AR agonists should be considered in protocols for ex vivo expansion of Treg before the transfer to patients in different medical applications. Frontiers Media S.A. 2012-07-05 /pmc/articles/PMC3389649/ /pubmed/22783261 http://dx.doi.org/10.3389/fimmu.2012.00190 Text en Copyright © 2012 Ohta, Kini, Ohta, Subramanian, Madasu and Sitkovsky. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
spellingShingle Immunology
Ohta, Akio
Kini, Radhika
Ohta, Akiko
Subramanian, Meenakshi
Madasu, Manasa
Sitkovsky, Michail
The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway
title The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway
title_full The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway
title_fullStr The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway
title_full_unstemmed The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway
title_short The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway
title_sort development and immunosuppressive functions of cd4(+) cd25(+) foxp3(+) regulatory t cells are under influence of the adenosine-a2a adenosine receptor pathway
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389649/
https://www.ncbi.nlm.nih.gov/pubmed/22783261
http://dx.doi.org/10.3389/fimmu.2012.00190
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